GNE7915

Protein target name:

LRRK2

Mechanism of action:

Competitive inhibitor

Recommended Concentration for use in cells:

Up to 100 nM

Probe Availability

MedChem Express (1351761-44-8)

Cayman (1351761-44-8)

Probe Information

Target and Probe Information

Target Details

Target class:

Protein kinase

Subclass:

TKL

HUGO ID:

HGNC:18618

Entrez gene ID:

120892

UNIPROT ID:

Q5S007

Target alias:

AURA17, DARDARIN, PARK8, RIPK7, ROCO2

Probe Details

Chemical Probes Portal ID:

CPP91

Probe alias:

GNE-7915

PubChem CID:

58539171

ChEMBL ID:

CHEMBL2178134

SMILES string:

CCNC1=NC(=NC=C1C(F)(F)F)NC2=C(C=C(C(=C2)F)C(=O)N3CCOCC3)OC

InChi Key:

XCFLWTZSJYBCPF-UHFFFAOYSA-N

Orthogonal probe:

MLi-2

PAINs evaluation:

PAINs free

Physico-chemical properties

NMR:

1H NMR (400 MHz, CDCl3) δ 8.44 (d, J = 12 Hz, 1H), 8.20 (s, 1H), 7.84 (s, 1H), 6.91 (d, J = 5.9 Hz, 1H), 5.21 (br s, 1H), 3.74−3.85 (m, 4H), 3.69−3.71 (m, 2H), 3.58−3.68 (m, 2H), 3.44 (br s, 2H), 1.33 (t, J = 7.2 Hz, 3H)

Validation in Cells and Model Organisms

In vitro validation

On target activity

Potency:

Ki(app)

1 nM

Off target activity

Potency assay (off target):

In vitro kinase assays, GNE7915 inhibited only 1 kinase >50% at 0.1 uM. In DiscoveRx Kinome scan of 451 kinases, GNE7915 inhibited only LRRK2, TTK, and ALK >30% at 0.1 uM.

In cell validation

On target activity in cells

Potency in cells:

IC50

9 nM

Potency assay (cells):

Inhibition of autophosphorylation

Target engagement assay (cells):

Indirect: inhibition of autophosphorylation

In vivo validation

Organism:

Rat

Dose:

0.5 mg/kg

Route of delivery:

Intravenous

Plasma half life:

3.1 hr

Systemic clearance:

8.3 mL/min/kg

Ratio of probe in organ to plasma (O:P):

0.5 (unbound fraction)

Fraction of probe bound to plasma protein:

0.5

Organ of Interest

Organ (O):

brain

Target engagement assay:

Indirect: inhibition of autophosphorylation

Primary Reference

Reference (doi):

10.1021/jm301020q

Reference (PMID):

22985112

Endorsed probe

The Chemical Probes Portal endorses this compound as chemical probe for use in cells and in model organisms.

SAB Rating

Rating for use in Cells

3 review(s)

Rating for use in Model Organisms

3 review(s)

SAB Members

SAB Comments

In vivo use will depend on application and delivery method: 15 mg/kg is suitable for IP, and 50 mg/kg suitable for oral delivery.

Jun 29 2016 - 8:02pm

This probe comes from a structure- and property-guided optimization of an earlier compound that was identified using a JAK2-based LRRK2-homology model. As such, JAK2 was used for selectivity standard during optimization. Having said that, most of the selectivity data in the original paper look respectable. According to Figure 6A of the original publication, a higher dose may be appropriate for oral administration than i.p.

Sep 6 2016 - 1:59pm

This reviewer would use GNE7915 in the cell-based setting with caution. The reasons are several fold: 1) Only biochemical selectivity was disclosed in the paper - no translation to selectivity in cell-based systems was presented. 2) The compound is an inhibitor of the target (biochemical Ki=1 nM) and TTK (biochemical Ki=53 nM) and ALK (biochemical Ki not disclosed, but >65% probe displaced at 100 nM in the KinomeScan evaluation). 3) GNE7915 inhibits several other kinases as 100 nM (>50% probe displacement at 100 nM in KinomeScan evaluation), and the identity of these other kinases was not disclosed. 4) In a Cerep panel, GNE7915 inhibits 5-HT2B (>70% inhibition at 10 uM). GNE7915 was described as a moderately potent inhibitor of 5-HT2B after functional follow-up, but inhibition data were not supplied. For in vivo studies, this reviewer would be very selective and only evaluate in the Sprague-Dawley strain of rats. The reasons are as follows: 1) No data with other species was presented. Importantly for a related molecule (compound 1 from the J. Med. Chem. manuscript), a high degree of variation between CNS exposures in mouse and rat was noted. Thus, in the absence of any mouse data for GNE-7915, users should not try to extrapolate data to other rodent species. Indeed, as GNE7915 was evaluated in Sprague Dawley rats only, interstrain variability in rats may also be possible. 2) Upon dosing of GNE7915 in rats, no effort was made to see if inhibition of the other kinases that are known to be 'hit' by GNE7915 occurred. 3) Upon dosing of GNE-7915 in rats, no effort was made to see if inhibition of 5-HT2B occurred.

Mar 30 2017 - 7:06pm

GNE7915

Probe Availability

Probe Information

Target Details

AURA17, DARDARIN, PARK8, RIPK7, ROCO2

Probe Details

Physico-chemical properties

In vitro validation

In cell validation

In vivo validation

Primary Reference

Supporting Organizations

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Search form

GNE7915

Probe Availability

Probe Information

Target Details

AURA17, DARDARIN, PARK8, RIPK7, ROCO2

Probe Details

Physico-chemical properties

In vitro validation

In cell validation

In vivo validation

Primary Reference

Supporting Organizations

Interested in supporting the portal?